The present invention relates generally to the intrauterine use of compliant polymeric substances in pregnant women to reduce the incidence of preterm birth comprising polymeric compositions selected for ability to prevent amniotic fluid leakage in cases of ruptured amniotic membranes and to provide a physical cervical barrier to migration of microbes, and optionally for ability to release therapeutic agents to prevent labor and/or infection.
In the United States, approximately 300,000 newborns are born prematurely every year, a figure that represents about 6% to 10% of all newborns. Preterm premature rupture of fetal membranes (PROM) is a factor in a majority of these births. About 20% of these premature infants die in the first month. Survivors may suffer short or long term morbidity involving every organ system. The hospitalization costs of the acute antepartum maternal care, the neonatal intensive care and the immediate care of the prematurely born infant, are enormous and often exceed $500,000 per case. Additional costs for care of the premature newborn continue to accrue after discharge from the hospital and potentially throughout the child""s life, including further care due to life long handicaps and the cost of lost productivity due to these handicaps.
The cause of premature labor or rupture of the fetal membranes is almost certainly multifactorial. One factor leading to PROM is breach of the cervical barrier that separates the vagina, which is colonized by a multitude of microbial families, from the sterile intrauterine environment. Such a breach of the cervical barrier can be due to the virulence of a given bacterial population or to deficits in immune or biochemical mechanisms that control the advance of microbes through the cervical canal. Alternatively, or concurrently, mechanical defects due to structural uterine or cervical abnormalities or prematurely occurring biochemical changes in the cervical tissue which lead to the premature opening of the cervical canal can cause or contribute to the process which ultimately culminates in PROM.
Two fundamental physiological processes in the uterine corpus and cervix are required for premature expulsion of the fetus to occur. In the uterine corpus (the body of the uterus), the muscular myometrium must change from a relaxed state, which is crucial to the continuation of pregnancy, to a state characterized by a rhythmic contractile activity that culminates in the expulsion of the products of conception. Meanwhile, the cervix must gradually yield, soften, efface and dilate. The softened and dilated cervix can no longer support the fetal chorioamniotic membranes, and eventually the membranes stretch and balloon through the cervical opening into the vagina. Occasionally, this ballooning action overcomes the tensile strength of the chorioamniotic membranes and leads to their rupture. Additionally, cervical softening and dilatation may allow the access of microbes into the lower uterine segment.
There are three main structural components of the cervix: smooth muscle, collagen, and the connective tissue xe2x80x9cground substancexe2x80x9d. The last is composed of the cervical glycosaminoglycans such as dermatan sulfate, chondroitin sulfate, and hyaluronic acid. Changes that take place in the collagen and in the connective tissue matrix of the cervix appear to be the primary factors allowing the cervix to soften and open in both normal and preterm labor. During pregnancy, dermatan and chondroitin sulfates bind tightly to collagen fibers and secure them in a dense collagen framework that ensures that the cervix remains firm and closed during normal pregnancy. The hyaluronic acid content is believed to play a role in the water retention capacity of the cervical tissue. At the end of pregnancy (or in events leading to premature labor), the cervical structure is completely remodeled so that it becomes soft and easily distensible. Collagen degradation becomes predominant as collagenase and other associated enzymes are activated and cervical dermatan sulfate concentrations diminish, causing disruption of the collagen framework and cervical matrix. The breakdown and loss of collagen and dermatan/chondroitin sulfates increase the flexibility and distensibility of the cervix, while the cervix also becomes swollen, soft and fragile due to increased hyaluronic acid and water content.(8)
With progressive softening, flexibility and distensibility of the cervical tissue, the mechanical support for the overlying chorioamniotic membranes gradually fails, leading to stretching of the fetal membranes in response to uterine activity and an increased risk of PROM. Mechanical stretching of the fetal membranes up-regulates the production of several amniotic factors, including prostaglandin E2 and interleukin-8. Stretch also increases the interstitial collagenases and matrix metalloproteinase- 1 (MMP- 1) within the membranes. (8) Prostaglandin E2 increases uterine irritability, decreases fetal membrane collagen, and increases production of MMP- 1 by human fibroblasts. (9,10) Interleukin-8, which is produced by amniotic and chorionic cells, is chemotactic for neutrophils and stimulates collagenase activity. The production of interleukin-8, which is present in low concentration in the amniotic fluid during the normal second trimester but in much higher concentrations late in gestation, is inhibited by progesterone. These processes leading to the PROM represent an acceleration or exaggeration of normal physiologic process, which in the normal pregnancy lead to a spontaneous rupture of membranes during labor.
There is indirect evidence that genital tract infection precipitates rupture of the membranes in animals and humans. In pregnant rabbits, cervical inoculation with Escherichia coil resulted in positive cultures for E. coli in the amniotic fluid and decidual tissue of ninety-seven percent of the treated animals and preterm delivery in half of the treated animals, while cervical inoculation of saline in control animals resulted in no infections or preterm births. (11) The identification of pathologic microorganisms in human vaginal flora soon after membrane rupture also support the idea that bacterial infection plays a role in the pathogenesis of premature membrane rupture. (12) Epidemiologic data demonstrate an association between colonization of the genital tract with group B streptococci, Chlamydia trachomatis, Neisseria gonorrhoeae, and the microorganisms that cause bacterial vaginosis and an increased risk of preterm premature rupture of the membranes. (13, 14).
Intrauterine infection may predispose women to rupture of the fetal membranes through any of several potential mechanisms, each of which induces degradation of the extracellular matrix. Proteases secreted by vaginal microbes can degrade collagen and weaken the fetal membranes. The host inflammatory response to bacterial infection, which is mediated by polymorphonuclear neutrophils and macrophages that are recruited to the site of infection, causes production of cytokines, matrix metalloproteinases, and prostaglandins. These substances further decrease the tissue support and the tensile strength of fetal membranes and also increase uterine activity, all of which contribute to the eventual rupture of the membranes.
Approximately 70% of premature births occur after PROM or pre-term labor (17). In spite of major advances in the fields of neonatal and perinatal medicine the outcome of PROM in the second or early third trimester is still associated with high mortality and morbidity. A major contributor to these sub-optimal outcomes following PROM is oligohydramnios (an inadequate amount of amniotic fluid surrounding the fetus). Oligohydramnios is a factor in perinatal asphyxia, chorioamnionitis, abruptio placenta, hypoplastic fetal lung, fetal compression abnormalities and amniotic band formation. The gestational age at which the rupture of membranes occurs and the persistence of oligohydramnios after PROM have a profound influence on perinatal outcome. The perinatal mortality rate in cases with documented rupture of membranes before 26 weeks of gestation, managed expectantly with bed rest, was recently reported to be 78.3%, while the perinatal mortality for newborns delivered at or beyond 26 weeks gestation was reported at 33.3%. (18).
The optimum management of PROM is not established but involves balancing the risks of active intervention (delivery) against watchful expectancy until fetal maturity or decompensation is documented. Recent clinical studies of PROM have documented that the risks of perinatal death from prematurity exceed the risks of infection from delayed delivery after PROM (23-26). Thus, expectant management is presently advocated by the overwhelming majority of perinatologists (27). However, attempts to manage patients with PROM in mid trimester have so far met with minimal success (18, 28-30). To successfully manage PROM, the problems of uterine contractions, infection and oligohydramnios, which are the chief contributors to perinatal mortality and morbidity, must be addressed. Present clinical management of PROM (18, 28-30) addresses the problem of uterine contractions by administering tocolytic therapy. However, the problems of infection and amniotic fluid leakage are not usually actively addressed. Patients are usually monitored for the development of these two complications of PROM without any attempts to prevent or actively treat these problems other than inducing delivery of the fetus.
Three clinical experience reports have described attempts to use fibrin glue to prevent leakage of amniotic fluid after PROM (31-33). Fibrin glue is composed of two componentsxe2x80x94fibrinogen and thrombin. When mixed together, the clotting cascade is initiated to form a fibrin clot or plug. Fibrin glue has been used widely in Europe since 1970 as a tissue sealant and hemostatic agent. Its use was mostly confined to trauma and surgical emergency situations where acute hemostatic control or cerebrospinal fluid leakage control was necessary. However, the glue was prepared commercially from pooled human blood and consequently carried a risk of hepatitis and HIV infections. In 1978 the Food and Drug Administration banned the use of commercially available fibrin glue because of its pooled human fibrinogen origin. Fibrin glue prepared from a patient""s own plasma may still be used in non-emergency situations when there is time to prepare the glue.
Although the fibrin glue sealing procedure was reported to be successful in patients with PROM, the total number of patients involved was very small and the results were not compared to control groups treated with standard therapy. Thus, the clinical usefulness of fibrin glue sealing in PROM, in terms of providing prolonged gestation and decreased perinatal morbidity and mortality, remains unproven. In addition, the procedure has several significant disadvantages and limitations. The process of preparing fibrin glue from autologous plasma is long and cumbersome and requires that the patient self-donate plasma and be back-transfused with her own red blood cells. The bonding and strength properties of such autologous fibrin glue vary widely among patients because the level of fibrinogen, the main component of the glue, varies among patients. The mechanical properties of the fibrin plug provide neither adequate physical support to the tissues nor a significant barrier to bacteria. The fibrin glue will also promptly lose effectiveness as it is degraded by the patient""s own enzymes. The rate of degradation varies greatly due to differences in fibrinolytic activity among each patient and thus makes it difficult to predict the length of time that the fibrin glue will remain effective as a sealant and also makes it almost impossible to determine an appropriate amount of potential additives, such as antibiotics or antithrombolytics, that might be incorporated into the glue. Finally, the almost instantaneous clotting of the fibrin glue upon contact of the fibrinogen and thrombin components limits the ability to tailor the shape of the fibrin glue plug (for example, to flow into uneven surface interstices and also to be shaped for optimal structural support for the chorioamniotic membranes and the lower uterine segment and internal cervical os) and renders the fibrin glue plug non-homogeneous in its composition and strength. In view of these limitations, autologous fibrin glue is not a wholly satisfactory substance for sealing of prematurely ruptured chorioamniotic membranes.
Thus, a need continues to exist for methods and devices or systems that reduce the incidence of preterm delivery, for example, by preventing the vaginal leakage of amniotic fluid after PROM, by providing local mechanical support to the cervix and fetal membranes, or by establishing a physical barrier to the passage of the bacteria from the vagina to the lower uterine segment and fetal membranes. A need also exists for a local pharmacological agent delivery system. Ideally, such methods and devices or systems would not require the patient to be confined in a hospital.
Of interest to the present invention are reports that hydrogels have been used for sealing of tissue [see, e.g., U.S. Pat. Nos. 5,900,245 or 5,800,373], in pleural or dural repair [Lyman et al., Ann. Biomat., 2:212 (1996); Alleyne et al., J. Neurosurg., 88:308-313 (1998)], in endoluminal gel paving of blood vessels [see, e.g., U.S. Pat. No. 5,749,915 and Slepian et al., Semin. Interv. Cardiol., 1: 103-16 (1996)], in pericardial patches [Blue et al., ASAIO Transactions, 37:M152-53 (1991)] and as wound dressings and implants [Corkhill et al., Biomaterials, 10:3-10 (1989)]. Also of interest is a report that heated flowable polymers may be used to occlude channels in mammalian tissue [U.S. Pat. No. 5,469,867].
Of further interest are reports that hydrogels or other polymers may be used to release biologically active agents [see, e.g., U.S. Pat. No. 5,879,713; Martin et al., Biomaterials, 19:69-76 (1998)], including intrauterine delivery of drugs [U.S. Pat. No. 4,188,951], delivery of basic fibroblast growth factor to skull bone [Tabata et al., Biomaterials, 19:807-815 (1998)], delivery of bone morphogenetic protein-2 (BMP-2) to skull bone [Hong et al., J. Biomater. Sci. Polym. Ed., 9:1001-1014 (1998)], release of cytarabine (ara-C) to plasma from back implants [Blanco et al., Biomaterials, 19:861-69 (1998); Gomez et al., J. Pharm. Pharmacol 50:703-712 (1998)], release of epidermal growth factor [Draye et al., Biomaterials, 19:99-107 (1998)], release of heparin [Nakayama et al., ASAIO Journal, 38:M421-24 (1992)] and delivery of antibiotics to the eye [Chetoni et al., Eur. J. Pharm. Biophann., 46:125-32 (1998)].
Also of interest are studies of the mechanical properties of hydrogels [Suggs et al., J. Biomater. Sci. Polym. Ed., 9:653-66 (1998); Anseth et al., Biomaterials, 17:1647-57 (1996); Oxley et al., Biomaterials, 14:1064-72 (1993); Watler et al., Biomaterials, 9:150-54 (1988)] and studies of the diffusion and release properties of hydrogels [see, e.g., Iza et al., J. Controlled Release, 52:41-51 (1998); Kikkinides et al., J. Controlled Release, 51:313-325 (1998); Andreopoulos et al., J. Biomater. Appl., 12:291-99 (1998); Merrill et al., Biomaterials, 14:1117-26 (1993); Trigo et al., Biomaterials, 15:1181-86 (1994)] and hydrogel composites [Cifkova et al., Biomaterials, 11:393-396 (1990), Lopour et al., Biomaterials, 11:397-402 (1990)].
The present invention provides a uterine cervix and intrauterine polymeric system on (adjacent to) chorioamniotic membrane comprising a first polymeric material. This first polymeric material may be adherent to the chorioamniotic membrane, may have an elongation at rupture similar to or greater than that of chorioamniotic membrane, or may be characterized by an elongation at rupture, elastic modulus, tensile stress and tensile modulus that provides sufficient physical support to reduce stretching of the chorioamniotic membrane into (or through) the uterine cervix during pregnancy. Preferably, the force required to rupture said first polymeric material is similar to or greater than that required to rupture chorioamniotic membrane. The first polymeric material may also form a physical barrier preventing migration of vaginal microbes into the uterus.
The first polymeric material is preferably a hydrogel. The polymeric material may further comprise a second polymeric composition located intracervically, and optionally may further comprise a third polymeric composition located in the vaginal portion of the cervix. The second and third polymeric compositions may be the same as or different from the first polymeric material.
The first, second or third polymeric compositions can release therapeutic amounts of pharmaceutical agents into the uterine and cervical area over a time period selected from the group consisting of 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks or more. For example, drug release may be provided by incorporation of microspheres comprising a pharmaceutical agent into said polymeric compositions. Suitable pharmaceutical agents include antibiotics, labor-inhibiting agents, tocolytic agents, prostaglandin inhibitors, anti-inflammatory agents, anti-proteolytic agents, estrogenic agents, progestogenic agents, steroid hormones, and any other substance beneficial to prolonging gestation.
The invention also provides methods for forming the polymeric material (system) of claim 1 comprising the steps of: contacting the lower uterine segment with a polymerizable solution and polymerizing said material to form said system, optionally further comprising the steps of administering a polymerizable composition into the cervix of a pregnant female, and polymerizing said composition.
Methods of the invention include methods for reducing the incidence of preterm birth comprising the steps of administering a polymerizable composition into the lower uterine segment of the uterus of a pregnant female, and polymerizing said composition. According to such methods, pregnancy is prolonged and preterm labor and birth is prevented. Females to be treated include females suffering from premature labor, suffering from premature rupture of fetal chorioamniotic membrane (PROM), and females at risk of preterm labor. Signs of risk of preterm labor include high levels of oncofetal fibronectin, documented high proteolytic activity, signs of cervical softening or ripening, a significantly shorter cervix, a prior history of cervical incompetence, cervical funneling, a prior history of preterm birth, and a prior history of PROM.
Numerous additional aspects and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of the invention which describes presently preferred embodiments thereof.